Looking beyond the dogma of genomic steroid action: insights and facts of the 1990s.

The genomic theory of steroid action has been the unquestioned dogma for the explanation of steroid effects over the past four decades. Despite early observations on rapid steroid effects being clearly incompatible with this theory, only recently has nongenomic steroid action been more widely recognized and led to a critical reappraisal of unsolved questions about this dogma. Evidence for nongenomic steroid effects is now coming from all fields of steroid research, and mechanisms of agonist action are being studied with regard to the membrane receptors and second messengers involved. A prominent example of a receptor/effector cascade for nongenomic steroid effects has been described for rapid aldosterone effects in various cell types, including lymphocytes and vascular smooth muscle cells. Rapid in vitro effects of aldosterone on the sodium proton antiport have been found in human lymphocytes, cultured vascular smooth muscle, and endothelial cells involving non-classical membrane receptors with a high affinity for aldosterone, but not for cortisol, and phosphoinositide turnover. Another important second messenger, [Ca2+]i, is consistently increased by aldosterone within 1-2 min. In vascular smooth muscle cells, calcium is released from perinuclear stores while in endothelial cells a predominant increase of subplasmalemmal calcium is seen. Effects are half-maximal at physiological concentrations of free aldosterone (0.1 nM), while cortisol is inactive up to 0.1 microM; the classical mineralocorticoid antagonist canrenone is ineffective in blocking the action of aldosterone. The data show that intracellular signaling for nongenomic aldosterone effects also involves calcium, but pathways of cell activation may vary between different cell types. Further evidence for nongenomic steroid effects is encountered presently for various groups of steroids such as neurosteroids, mineralocorticoids, vitamin D3, and sex hormones. Future research will have to target the cloning of the first membrane receptor for steroids and evaluate the clinical relevance of these rapid steroid effects.